EP1941266A1 - Procede, systeme et progiciel permettant d'identifier de façon specifique des paires de reaction associees par des differences neutres specifiques - Google Patents

Procede, systeme et progiciel permettant d'identifier de façon specifique des paires de reaction associees par des differences neutres specifiques

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Publication number
EP1941266A1
EP1941266A1 EP06775115A EP06775115A EP1941266A1 EP 1941266 A1 EP1941266 A1 EP 1941266A1 EP 06775115 A EP06775115 A EP 06775115A EP 06775115 A EP06775115 A EP 06775115A EP 1941266 A1 EP1941266 A1 EP 1941266A1
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EP
European Patent Office
Prior art keywords
mass
mass spectrum
spectrum
shifted
sequence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP06775115A
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German (de)
English (en)
Other versions
EP1941266A4 (fr
EP1941266B1 (fr
Inventor
Yves Le Blanc
Nic Bloomfield
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DH Technologies Development Pte Ltd
Original Assignee
MDS Analytical Technologies Canada
Applera Corp
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Publication of EP1941266A1 publication Critical patent/EP1941266A1/fr
Publication of EP1941266A4 publication Critical patent/EP1941266A4/fr
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Classifications

    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/0027—Methods for using particle spectrometers
    • H01J49/0036—Step by step routines describing the handling of the data generated during a measurement
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/20—Identification of molecular entities, parts thereof or of chemical compositions
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/004—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn
    • H01J49/0045—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn characterised by the fragmentation or other specific reaction

Definitions

  • the invention relates to mass spectrometry and to a method of comparing mass spectra.
  • Mass spectrometers are often used to analyze test samples that include many different species or compounds of interest.
  • MS/MS analysis is used to (1) select a precursor or parent ion of interest, (2) fragment that ion, and then (3) conduct further analysis of these fragment ions.
  • an MS/MS system might include a first ion guide, which axially ejects the parent ion of interest into a collision cell. Once in the collision cell, the parent ion is fragmented and the fragments are ejected to a downstream mass spectrometer which can be used to identify the fragment ions of interest. Optionally, these fragment ions could be further fragmented.
  • a method of processing mass spectrographic data regarding reaction pairs in an ion sample comprises (a) obtaining a first mass spectrum of the ion sample; (b) obtaining a second mass spectrum of the ion sample; (c) selecting a neutral difference; and, (d) shifting the second mass spectrum by the neutral difference relative to the first mass spectrum of the ion sample to provide a shifted mass spectrum, and then comparing the shifted mass spectrum with the first mass spectrum of the ion sample to determine at least one reaction pair based on the neutral difference.
  • a mass analysis system for obtaining and processing mass spectrographic data regarding reaction pairs in an ion sample.
  • the mass analysis system comprises (a) a mass spectrometer system for obtaining a first mass spectrum and a second mass spectrum of the ion sample; (b) a neutral difference selector for selecting a neutral difference; and, (c) a processor for shifting the second mass spectrum by the neutral difference relative to the first mass spectrum of the ion sample to provide a shifted mass spectrum and then comparing the shifted mass spectrum with the first mass spectrum of the ion sample to determine at least one reaction pair based on the neutral difference.
  • a computer program product for processing mass spectrographic data regarding the reaction pairs in an ion sample.
  • the computer program product comprises a recording medium and means recorded on the recorded medium to instruct the computer system to perform the steps of; (a) receiving a first mass spectrum of the ion sample; (b) receiving a second mass spectrum of the ion sample; (c) selecting a neutral difference; and, (d) shifting the second mass spectrum by the neutral difference relative to the first mass spectrum of the ion sample to provide a shifted mass spectrum and then comparing the shifted mass spectrum with the first mass spectrum of the ion sample to determine at least one reaction pair based on the neutral difference.
  • FIG. 1 in a block diagram, illustrates a liquid chromatography, mass spectrometry (LCMS) system in accordance with an aspect with the present invention
  • Figure 2 in a block diagram, illustrates the controller of Figure 1 ;
  • Figure 3 in a process flow diagram, illustrates a method of processing mass spectrographic data regarding parent/fragment pairs in an ion sample in accordance with a further aspect of the invention
  • Figures 4a and 4b illustrate scans of a Bromocriptine-containing ion sample at different levels of fragmentation obtained in accordance with an implementation of the method of Figure 3;
  • Figures 5a and 5b illustrate mass spectra derived from the mass spectra of Figures 4a and 4b in accordance with a particular implementation of the method of Figure 3 using a neutral loss of 98;
  • Figures 6a and 6b illustrate mass spectra derived from the mass spectra of Figures 4a and 4b in accordance with a further particular implementation of the method of Figure 3 using a neutral loss of 24;
  • Figure 7 in a process flow diagram, illustrates a method of processing mass spectrographic data regarding parent/fragment pairs in an ion sample in accordance with a further aspect of the present invention.
  • the mass analysis system 20 comprises a chromatography column 22 coupled to a mass spectrometer component 24, which may be either a single mass spectrometer, or a tandem mass spectrometry system - A -
  • a data-processing system and controller 26 controls the operation of the MS component 24 and extracts information from the mass spectra obtained by the MS component 24.
  • the LC portion of the LC/MS/MS system is optional as the ions could also be provided by infusion, or other means, such as, for example an ion source such as Matrix Assisted Laser Desorption/lonization (MALDI).
  • MALDI Matrix Assisted Laser Desorption/lonization
  • the data processing system and controller 26 comprises a neutral loss (NL) selector for selecting a particular neutral loss of interest.
  • NL neutral loss
  • the neutral loss selector 28 is linked with a computation module 30 to provide the neutral loss or neutral losses selected to this computation module 30.
  • the computation module 30 in turn comprises a shift function 32, a comparison function 34 and a subtraction function 36.
  • the data processing system and controller 26 may be provided by a general purpose computing device, such as for example without limitation, a desk top computer, slim line computer, laptop computer, workstation computer or other similar computer device.
  • a general computing system may include the following components; a network interface, a display, a memory store, input means, a central processing unit and a bus.
  • the general purpose computing system may communicate with a network, which may also be connected to other similar computing systems.
  • the general computing system may be configured to provide the components of the data processing system and controller 26 shown in Figure 2 by a suitable software product including a recording medium, together with means recorded on the recording medium to configure the memory store and central processing unit of the general unit computing device to provide the neutral loss selector 28, computation module 30, shift function 32, comparison function 34 and subtraction function 36 described above.
  • the data processing system and controller 26 may be provided by a dedicated computing device with no need for external software to configure it suitably.
  • a data processing system and controller 26 may not be linked to the mass spectrometer component 24, instead being used for post-acquisition processing of the data previously stored from the mass spectrometer system.
  • the MS component 24 obtains two mass spectrograph ⁇ scans for the same sample.
  • One scan is a low orifice (low fragmentation) scan in which large amounts of the parent ion will be present, together with small amounts of fragment ions.
  • the second large orifice (high fragmentation) scan is conducted with the same ion sample. Due to fragmentation, the mass spectrum obtained from the high fragmentation scan will contain less of the parent ion and more of the fragment ions than the mass spectrum obtained from the low fragmentation scan.
  • a collision cell may also be used to acquire mass spectra at different levels of fragmentation.
  • a first mass analyzer operated in RF-only mode may focus ions into a collision cell operated at a minimal collision energy for transmission of low fragmentation ions and at higher collision energy to generate fragmentation ions. Then, from the collision cell, the ions can be provided to a second mass analyzer, or ejected back to the first mass analyzer, for mass analysis of the population of ions sequentially generated in the collision cell (i.e., low fragmentation ions and high fragmentation ions).
  • mass spectra are shrunk by subtracting out zero values in the spectra.
  • these zero values are retained in both the low fragmentation mass spectrum and the high fragmentation mass spectrum for reasons that will be outlined below.
  • the low fragmentation mass spectrum and the high fragmentation mass spectrum are communicated to the computation module 30 of the data processing system and controller 26.
  • the subtraction function 36 subtracts the low fragmentation mass spectrum from the high fragmentation mass spectrum to obtain a differential mass spectrum. This step removes a lot of the noise that is common to both the low fragmentation mass spectrum and the high fragmentation spectrum, thereby increasing the relative mass signals for the fragment ion of interest in the differential mass spectrum, as the low fragmentation mass spectrum will not have as much of this fragment ion as the high fragmentation mass spectrum. According to some embodiments, this subtraction step can be bypassed.
  • the MS component 24 may not be necessary to clean up the ion sample by subtracting the low fragmentation mass spectrum from the high fragmentation mass spectrum. This could be achieved, for example, by extending the LC separation step in the liquid chromatography column 22 upstream from the mass spectrometer component 24.
  • a neutral loss of interest is selected by either (1) a user through a user input means, or (2) automatically by the system as it runs through a number of possible neutral losses of interest.
  • the shift function 34 shifts the mass signals of the differential mass spectrum by the selected neutral loss, such that the mass signals for the fragment ions in the differential mass spectrum now align with the mass signals for the parent ion in the minimal fragmentation mass spectrum. Then, the mass signals of the shifted differential mass spectrum are compared with the aligned or corresponding mass signals of the low fragmentation mass spectrum by the comparison function 36.
  • this comparison multiplies the aligned mass signals of the shifted differential mass spectrum and the low fragmentation mass spectrum, such that, for example, the mass signals for fragment ions in the shifted differential mass spectrum are multiplied by the mass signals for the parent ions in the low fragmentation mass spectrum.
  • noise is further removed as unless two mass signal peaks align, the resulting product would be very close to zero.
  • the product spectrum obtained by multiplying the shifted differential mass spectrum with the minimal fragmentation mass spectrum will typically contain fewer peaks, making it easier to select the ion of interest for further processing.
  • a reference spectrum is obtained from a first MS scan of an ion sample.
  • a high fragmentation mass spectrum from a second MS scan is obtained for the ion sample.
  • fragmentation will be induced for the second MS scan either at source or in a collision cell, such that the mass spectrum of the second MS scan will be fragmented to a much greater extent than the reference spectrum obtained from the first MS scan.
  • FIG. 4a and 4b mass spectra obtained from a low orifice scan of an ion sample containing Bromocriptine are illustrated. Specifically, Figure 4a illustrates the reference spectrum (the low orifice or low fragmentation spectrum) while Figure 4b illustrates the high fragmentation mass spectrum (from a high orifice scan). Both of these mass spectra are obtained from the same ion sample.
  • a neutral loss mass is selected. Optionally, several neutral losses may be selected by a user, or the selection of these neutral losses may be automated.
  • step 46 a differential spectrum is obtained by subtracting the reference spectrum obtained in step 40 from the high fragmentation spectrum obtained in step 42. In doing so, it is important to retain the "zeros" in both initial spectra in order to provide proper alignment of mass signals.
  • step 48 of the method of Figure 3 the differential spectrum determined in step 46 is shifted by the neutral loss selected in step 44 such that the mass signals for fragments indicated by the neutral loss selected are aligned with the mass signals for the parent ions in the reference spectrum. Then, this shifted differential spectrum obtained in step 48 is, in step 50, multiplied with the reference spectrum.
  • This step of multiplying the two mass spectra involves multiplying each mass signal in one spectrum with the corresponding aligned mass signal in the other spectrum to obtain a probability mass spectrum. Such a probability mass spectrum is illustrated in Figure 5b. From Figure 5b, it is apparent that this probability mass spectrum indicates the most probable associated parent/fragment pairs for the neutral loss selected in step 44.
  • the peak intensity in the probability mass spectrum shown in Figure 5b is proportional to the probability of the ions in the initial spectra representing parents and fragments for that neutral loss mass.
  • the selection of the neutral loss mass parent/fragment pairs occurs in step 52. This step may be performed manually, by selecting the mass signal peaks in the probability mass spectrum. Alternatively, this step may be automated by selecting all mass signal peaks in the probability mass spectrum that are over a selected threshold in height. In either case, the parent/fragment pairs can then be determined. Typically, these parent/fragment pairs will reflect, at least in the case of biological samples, the presence of related classes of compounds (e.g. metabolites or post- translational modification).
  • step 54 the intensities of all of the parent/fragment pairs can be summed to determine a total ion current plot (TIC).
  • step 56 the precursor corresponding to the parent/fragment pair can be selected as the ion for subsequent downstream MS/MS analysis. Then, optionally the method can return to steps 40 and 42 for a new ion sample.
  • a new neutral loss may be selected and steps 48 to 56 repeated for the same ion sample for this new neutral loss.
  • the mass spectra of Figures 4a and 4b may be analyzed using a different selected neutral loss of 24.
  • the differential mass spectrum shown in Figure 6a will, of course, be the same as the differential mass spectrum previously determined with a selected neutral loss of 98. However, when this differential mass spectrum is shifted by the neutral loss and then multiplied by the mass spectrum of Figure 4a, then a new probability mass spectrum, shown in Figure 6b, will be obtained. This probability mass spectrum enables different parent/fragment pairs - identified by the neutral loss of 24 - to be identified.
  • the ion signal density in the probability mass spectrum shown in Figure 6b is proportional to the probability of the ions in the initial spectra representing parents and fragments for a neutral loss of 24.
  • the intensities of all of the parent/fragment pairs can then be summed to determine the TIC.
  • the precursor corresponding to the parent/fragment pair of a given neutral loss can be selected as the ion for subsequent downstream MS/MS analysis.
  • the first mass spectrum shown in Figure 4a comprises a sequence of first mass signals defined over a mass axis (the X axis in Figure 4a) such that each mass signal in Figure 4a represents an associated signal magnitude for an associated mass on the mass axis.
  • the mass spectrum of Figure 4b comprises a sequence of mass signals defined over the mass axis (again the X axis) such that each mass signal represents an associated signal magnitude for an associated mass on the mass axis.
  • the mass spectrum of Figure 4a is subtracted from the mass spectrum of Figure 4b. This involves subtracting each individual mass signal in the sequence of mass signals of Figure 4a from a corresponding aligned (at the same point along the X axis) mass signal in the sequence of mass signals of the mass spectrum of Figure 4b.
  • the differential spectrum obtained by subtracting the mass spectrum of Figure 4a from the mass spectrum of Figure 4b is shifted by the neutral loss selected in step 44.
  • This entails displacing a sequence of mass signals of the differential mass spectrum along the mass axis by the neutral loss relative to the sequence of mass signals of the mass spectra of either Figure 4a or Figure 4b.
  • it may optionally be the mass spectra of Figure 4a or Figure 4b that is shifted and not the mass signals of the differential mass spectrum provided these mass signals are shifted by the neutral loss relative to each other.
  • the sequence of mass signals of the shifted differential mass spectrum is compared with a sequence of mass signals of one of the mass spectra of Figure 4a and 4b to determine at least one parent/fragment pair associated with neutral loss of interest.
  • an individual shifted differential mass signal in the sequence of shifted differential mass signals of the shifted differential mass spectrum is compared with the individual mass signal in the sequence of mass signals of the first mass spectrum that is aligned with the individual shifted differential mass signal along the mass axis of the two mass spectra. In some embodiments, as described above, this involves multiplying the individual shifted differential mass signal with the corresponding aligned individual mass signal of Figure 4a or 4b. Preferably, this is done for all of the aligned mass signals for these two mass spectra.
  • FIG. 7 there is illustrated in a process flow diagram a method of processing mass spectrographic data regarding parent/fragment pairs in an ion sample in accordance with a further aspect of the invention.
  • This further aspect of the invention involves multiple processing cycles for both the low fragmentation or reference spectrum and the high fragmentation spectrum. That is, in the aspect of the invention illustrated in Figure 7, the ion sample for both the low fragmentation and high fragmentation mass spectra is processed or cycled several times.
  • a T n- i reference mass spectrum is obtained from a mass spectrum scan of the ion sample in step 60, and the T n reference spectrum is obtained from the mass spectrum scan of the ion sample in the next cycle in step 62.
  • a T n- I high fragmentation mass spectrum is obtained from a high fragmentation mass spectrum scan for the ion sample in step 64, and, subsequently, a T n high fragmentation mass spectrum is obtained from the high fragmentation mass spectrum scan of the ion sample in the next cycle in step 66.
  • fragmentation will typically be induced for the high fragmentation mass spectrum scans either at source or in a collision cell, such that the high fragmentation mass spectrums obtained in steps 64 and 66 will be a result of ions being fragmented to a much greater extent than the reference spectrums obtained from the first mass spectrum scans in steps 60 and 62.
  • a filtered reference mass spectrum is obtained by subtracting the T n- i mass spectrum obtained in step 60 from the T n mass spectrum obtained in step 62.
  • a filtered high fragmentation mass spectrum is obtained in step 70 by subtracting the T n- i high fragmentation mass spectrum obtained in a step 64 from the T n high fragmentation mass spectrum obtained in step 66.
  • Steps 68 and 70 help to clean up the reference and high fragmentation mass spectra by filtering out some of the noise that is common to both the T n- i and T n mass spectrum scans.
  • a neutral loss mass is selected.
  • several neutral losses may be selected by a user, or the selection of these neutral losses may be automated.
  • step 74 a differential spectrum is obtained by subtracting the filtered or background subtracted mass spectrum (BSMS) reference spectrum obtained in step 68 from the filtered or BSMS high fragmentation mass spectrum obtained in step 70.
  • BSMS background subtracted mass spectrum
  • step 76 the differential spectrum obtained in step 74 is shifted by the neutral loss selected in step 72 such that the mass signals for fragments indicated by the neutral loss selected are aligned with the mass signals for the parent ions in the BSMS reference spectrum.
  • step 78 can be implemented on its own or one can further clean the spectra by implementing steps 74 and 76.
  • step 78 the BSMS fragment spectrum obtained in step 70 is shifted by the neutral loss mass relative to the reference mass spectrum. Whichever path taken from step 72, whether through step 78 on the one hand, or steps 74 and 76 on the other, the method of Figure 7 then proceeds to step 80.
  • step 80 either the shifted BSMS high fragmentation mass spectrum obtained in step 78, or the shifted differential mass spectrum obtained in step 76 is multiplied by the reference mass spectrum generated in either step 62 or step 68.
  • this step of multiplying the two mass spectra involves multiplying each mass signal in one mass spectrum with the corresponding aligned mass signal in the other mass spectrum to obtain a probability mass spectrum.
  • the mass signal peak intensity is proportional to the probability of the ions in the initial mass spectra input in step 80 representing precursor ions associated with a parent/fragment pair for that neutral loss mass.
  • the most probable parent/fragment pairs for the selected neutral loss are themselves selected.
  • the intensities of all of the parent/fragment pairs can be summed to determine a TIC.
  • parent/fragment pairs can be selected as the precursors for subsequent downstream MS/MS analysis.
  • the method can return to steps 60, 62, 64, 66 for a new ion sample.
  • steps 84 and 86 a new neutral loss may be selected and steps 74 to 86 repeated for this new neutral loss.
  • reaction pairs may be generated.
  • the parent/fragment pairs may be generated, for example, by fragmentation via collision, while the adduct pairs can be formed via reaction in gas phase.
  • the description has for the most part focused on instances in which the minimal fragmentation scan is acquired first, and the higher fragmentation scan subsequently acquired. This can clearly be advantageous in some situations as the same ions can be scanned both before and after fragmentation.
  • the high fragmentation scan may be obtained before, or at the same time as, the low fragmentation scan. All such modifications or variations are believed to be within the sphere and scope of the invention as defined by the claims appended hereto.

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Abstract

Selon l'invention, un premier spectre de masse et un second spectre de masse du même échantillon peuvent être analysés afin de déterminer des paires de réaction. Pour déterminer ces paires de réaction sur la base d'une différence neutre choisie, on modifie le second spectre de masse au moyen de la différence neutre par rapport au premier spectre de masse afin d'obtenir un spectre de masse modifié. Le spectre de masse modifié est ensuite comparé au premier spectre de masse de l'échantillon afin de déterminer la paires de réaction sur la base de la différence neutre.
EP06775115.6A 2005-10-28 2006-08-16 Procede, systeme et progiciel permettant d'identifier de façon specifique des paires de reaction associees par des differences neutres specifiques Active EP1941266B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/260,222 US7417223B2 (en) 2005-10-28 2005-10-28 Method, system and computer software product for specific identification of reaction pairs associated by specific neutral differences
PCT/CA2006/001340 WO2007048218A1 (fr) 2005-10-28 2006-08-16 Procede, systeme et progiciel permettant d'identifier de façon specifique des paires de reaction associees par des differences neutres specifiques

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EP1941266A1 true EP1941266A1 (fr) 2008-07-09
EP1941266A4 EP1941266A4 (fr) 2011-09-07
EP1941266B1 EP1941266B1 (fr) 2020-05-13

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US (1) US7417223B2 (fr)
EP (1) EP1941266B1 (fr)
JP (1) JP5203954B2 (fr)
CA (1) CA2629746A1 (fr)
WO (1) WO2007048218A1 (fr)

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Also Published As

Publication number Publication date
EP1941266A4 (fr) 2011-09-07
US20070096021A1 (en) 2007-05-03
CA2629746A1 (fr) 2007-05-03
JP5203954B2 (ja) 2013-06-05
JP2009513954A (ja) 2009-04-02
WO2007048218A1 (fr) 2007-05-03
US7417223B2 (en) 2008-08-26
EP1941266B1 (fr) 2020-05-13

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